1. Field of the Invention
The present invention relates to a method for therapy of rheumatoid arthritis. In particular, the present invention relates to a therapeutic method for rheumatoid arthritis by using a AP-1 oligonucleotide for inhibiting the intracellular signal of the c-fos gene expression product.
2. Description of the Related Art
Chronic rheumatoid arthritis (RA) is still one of many intractable diseases of which the cause is not as yet known, though the morbidity rate is as high as 0.3% of the population.
The process in RA is considered to be divided into the following 3 stages, and practically there are evidences that those processes are ongoing in the articular synovial membrane of RA (E. D. Harris, Jr., N. Engl. J. Med., 322: 1277-1289, 1990; S. Shiozawa and K. Shiozawa, Scand. J. Rheumatol. Suppl., 74:65-72, 1988). At the 1st stage, an unknown pathogenic factor reaches the articular synovial membrane from blood to initiate immune response at the articular region. At the 2nd stage, macro-phages, lymphocytes, neutrophils and so on infiltrate from blood to develop chronic inflammation. At the 3rd stage, i) cartilage matrix is degradated and digested by protease released from the inflamed synovial membrane; ii) cartilage and bone are destroyed by pannus derived from inflammatory granulation tissue; and iii) cartilage cells per se are activated to degradate peripheral matrix, and so on; such multiple progresses result in destruction and deformation of the joint.
In such an articular lesion of RA, two species of cells, i.e., T cells which are responsible for immunological memory to response specifically to antigens, and mesenchymal cells in synovial membrane which participate directly in the articular destruction, are considered to be basically important. Among them, it has been found that the latter mesenchymal cells are major components for pannus and produce cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), etc., which play an important role in joint inflammation of RA, to actively participate in destruction of the joint (S. Shiozawa, et al., Arthritis Rheum., 26:472-478, 1983). Thus, the RA is considered to be caused first by antigen-specific response involving T cells. It is further considered that at the stage at which the inflammation becomes lentus to result in a chronic condition, growth factors, cytokines, etc. are produced in large quantities to strongly activate the synovial cells of the articular region, particularly mesenchymal cells.
It is considered that when the synovial membrane is activated, then the cell-mediated articular destruction progresses automatically to some extent. On the other hand, a protooncogene c-fos, among genes involved in cell growth, is characterized by being continuously expressed in mesenchymal cells, particularly such as macrophages or synovial cells, without any stimulation. Pannus being composed of synovial cells is semi-tumor-like granulation tissue which may be described as “transforming”. In practice, when experimental arthritis was induced in H2-c-fos transgenic mice overexpressing human c-fos gene, the articular destruction was produced only by the mesenchymal cells of synovial membrane without infiltration of lymphocytes (T cells) (S. Shiozawa and T. Tokuhisa, Sem. Arthritis Rheum., 21:267-273, 1992). This means that over expression of the c-fos gene by gene manipulation gave the nearly autonomic proliferation potency to the mesenchymal cells of synovial membrane, and it was demonstrated that the activated synovial cells invaded as pannus into cartilage matrix (S. Shiozawa, et al., J. Immunol., 148:3100-3104, 1992). Moreover, it was found that the c-fos gene afforded peculiar morphological transformation and proliferation potency to human synovial cells, that when the human c-fos gene was continuously expressed in osteoblasts, the synthesis of bone matrix collagen was inhibited (Y. Kuroki, et al., J. Rheumatol., 20:422-428 (1993), and that osteoclastic bone resorption mediated by osteoblasts was significantly promoted (Y. Kuroki, et al., Biochem. Biophys. Res. Commun., 182:1389-1394, 1992). In other words, it was found that the basic and major pathological condition of RA, i.e., “proliferation of synovial cells” and “osteoporosis” in periarticular bone, could be reproduced experimentally by means of merely promoting the expression of c-fos gene.